The long-term objective of the research is to understand the mechanism of general anesthesia, relating specific molecular- and cellular-level targets to their network- and behavioral-level consequences. This proposal focuses on the role of hippocampal GABAA receptors in the suppression of learning and memory by the general anesthetic etomidate. Three specific aims test the hypothesis that etomidate blocks synaptic plasticity and memory by targeting interneurons in the hippocampus, interrupting disinhibitory circuits that are essential to these processes. Aim 1) Test the role of GABAAR ?2 subunits in suppression of synaptic plasticity and memory by etomidate, studying mice that carry the ?2-N265M mutation and measuring the effects of etomidate on LTP in vitro and memory in vivo. Aim 2) Determine whether removing ?5-GABAARs from specific classes of interneurons interferes with the ability of etomidate to suppress synaptic plasticity and memory, using Cre-driver lines targeting all interneurons (GAD65) or specific subsets of interneurons (VIP, CR, PV, CCK, SOM, O-LM). Aim 3) Measure the effects of etomidate on disinhibitory circuits in wild type and genetically modified mice, recording from specific interneurons to identify relevant inhibitory processes (i.e. those that incorporate ?5- and ?2-GABAARs), focusing our experiments on those classes of interneurons that are found to contribute most strongly, and manipulating disinhibitory circuits directly using optogenetic methods to reproduce or counteract the effects of etomidate on LTP in vitro and learning in vivo. The information that we will learn will aid in the development of improved methods for detecting and treating undesired events such as awareness with recall or persistent memory impairment that sometimes follows anesthesia. It also will help us understand the neural systems that are in place to control learning and memory in the healthy brain, how these systems are altered in certain disease states, and how they might be manipulated to improve memory in patients.